Methamphetamine (METH) dependence is prevalent in several regions of the US and has serious medical and social consequences. Several psychosocial interventions have shown moderate efficacy while no medication has shown robust efficacy for treating this disorder to date. Thus, novel medications development strategies for treating METH dependence are needed. Genetically mediated metabolic factors have been shown to impact vulnerability for drug dependence, with extensive metabolizers (EMs) typically demonstrating a greater risk for and severity of dependence on drugs such as nicotine and certain opioid analgesics than poor metabolizers (PMs). METH is initially metabolized via the cytochrome P450 2D6 (CYP2D6) enzyme system, which has several clinically relevant genetic variants; however, to our knowledge, the impact of this metabolic factor on the abuse liability of METH has not been extensively examined. A recent study showed that there was a significantly higher prevalence of EMs than PMs in Japanese participants who were METH dependent relative to those who were not. In addition, the prevalence of METH use is much lower among African Americans than Caucasians. Although reasons for this difference may include limited access to the drug and social beliefs, genetics could contribute to these racial divergences, in that African Americans have double the prevalence of PMs with CYP2D6. Thus, we hypothesize that genetically mediated metabolic factors modify METH preference and that pathways identified through genetic differences may provide effective pharmacological targets for medications development efforts. The specific aims of this project are to 1) determine the interaction between CYP2D6 phenotype and response to METH; 2) determine the role of CYP2D6 in behavioral/pharmacokinetic response to METH by testing the behavioral effects of agents that serve as positive (codeine) and negative (caffeine) controls for CYP2D6 phenotype. To this end, 20 healthy volunteers (aged 18-50) will be stratified by CYP2D6 phenotype after undergoing an 8-hr debrisoquine urinary recovery ratio test, and undergo five sessions in which METH (10 mg/70 kg, P.O. and either 5 or 15 mg/70 kg, PO), caffeine (500 mg/70 kg), codeine (120 mg/70 kg) or placebo is administered in random order. During each experimental session, the following measures will be assessed: 1) self-reported positive and negative subjective effects; 2) performance effects, as measured by reaction time, coordination, and cognitive impairment; 3) cardiovascular effects, as a measure of toxicity; and 4) pharmacokinetic profile, as measured by serum levels of drug and drug metabolite over time. These measures will provide a wide profile of effects to determine whether any effects are impacted by phenotype. These results will identify whether metabolic factors impact the response to METH as they do for other classes of drugs, provide preliminary data for larger clinical trials examining the interaction between genetic factors mediating both pharmacokinetic and pharmacodynamic effects of METH, and potentially guide novel medications development strategies for treating METH dependence.